Hepatobiliary delivery of polyaminopolycarboxylate chelates: synthesis and characterization of a cholic acid conjugate of EDTA and biodistribution and imaging studies with its indium-111 chelate

Abstract

A conjugate in which the steroid nucleus of cholic acid was linked to EDTA via an 11-atom spacer was obtained by reacting the succinimidyl ester of cholic acid with the amine formed by reaction of a benzyl isothiocyanate derivative of EDTA with N-(tert-butoxycarbonyl)ethylenediamine and subsequent deprotection. Potentiometric titration studies with model complexes showed that the EDTA moiety retained the ability to form 1:1 chelates of high thermodynamic stability, although formation constants were some 3-4 log K units lower for complexes of the conjugate than for the analogous chelates with underivatized EDTA. A complex formed between the cholic acid-EDTA conjugate and 111InIII was clearly rapidly into the liver when injected iv into mice, with subsequent excretion from the liver into the gastrointestinal tract being complete within 1 h of injection. Radioscintigraphic imaging studies conducted in a rabbit given the 111In-labeled conjugate also showed early liver uptake followed by rapid clearance from the liver into the intestine, with good visualization of the gallbladder in images obtained at 20-25 min postinjection. It is concluded that conjugation to cholic acid provides a useful means for the hepatobiliary delivery of EDTA chelates that otherwise exhibit predominantly extracellular distribution and renal clearance.

Targeted T1 Magnetic Resonance Imaging Contrast Enhancement with Extraordinarily Small CoFe2O4 Nanoparticles

“…7 Contrast agents for detecting tissue abnormalities, however, must be able to cross the hepatocyte membrane and eventually be excreted via bile. 64 Bile acids, amphipathic molecules composed of a sterol scaffold with hydroxyl groups and a carboxyl-terminated side chain, 34 are transported to and from the liver via the enterohepatic circulation system and thus are ideal candidates for use as liver transport vehicles. Anelli et al 65 tested whether cholic acid, cholylglycine, or cholyltaurine linked to Gd-DOTA chelates could encourage hepatospecificity and found that cholic acid was an efficient carrier for uptake by hepatocytes.…”

Metal-Based Complexes as Pharmaceuticals for Molecular Imaging of the Liver

“…Another approach is to exploit the imaging potential of bile acids, since these are natural ligands recognized by the liver [162]. Thus far, attempts have focused on 99m Tc and 111 In complexes of bile acid conjugates, which have shown hepatobiliary uptake and excretion [162,163].…”

Bile acid transport systems as pharmaceutical targets

“…The dipivaloylester of ursodeoxycholylcarboxymethylglycine was excreted in the bile mainly BILE ACID TRANSPORT SYSTEMS 721 as the dianion, suggesting its usefulness as a prod rug for calcium gallstone therapy [59]. To obtain a liverselective -y-emitting scintigraphic agent, cholic acid was linked via an l l-atom spacer with EDT A capable of complexing III In functions in the bile acid sidechain [60] (Fig.4, XIII). After intravenous application, the lll-InlII-EDTA-bile acid conjugate containing 4-carboxylic functions in the side-chain was rapidly cleared into the liver with completion of secretion within 1h.…”